Hepatic iron overload and hepatocellular carcinoma

The liver is the main storage site for iron in the body. Excess accumulation of iron in the liver has been well-documented in two human diseases, hereditary hemochromatosis and dietary iron overload in the African. Hepatic iron overload in these conditions often results in fibrosis and cirrhosis and may be complicated by the development of hepatocellular carcinoma. Malignant transformation usually occurs in the presence of cirrhosis, suggesting that free iron-induced chronic necroinflammatory hepatic disease plays a role in the hepatocarcinogenesis. However, the supervention of hepatocellular carcinoma in the absence of cirrhosis raises the possibility that ionic iron may also be directly hepatocarcinogenic. Support for this possibility is provided by a recently described animal model of dietary iron overload in which iron-free preneoplastic nodules and hepatocellular carcinoma developed in the absence of fibrosis or cirrhosis. The mechanisms by which iron induces malignant transformation have yet to be fully characterized but the most important appears to be the generation of oxidative stress. Free iron generates reactive oxygen intermediates that disrupt the redox balance of the cells and cause chronic oxidative stress. Oxidative stress leads to lipid peroxidation of unsaturated fatty acids in membranes of cells and organelles. Cytotoxic by-products of lipid peroxidation, such as malondialdehyde and 4-hydroxy-2′-nonenal, are produced and these impair cellular function and protein synthesis and damage DNA. Deoxyguanosine residues in DNA are also hydroxylated by reactive oxygen intermediates to form 8-hydroxy-2′-deoxyguanosine, a major promutagenic adduct that causes G:C to T:A transversions and DNA unwinding and strand breaks. Free iron also induces immunologic abnormalities that may decrease immune surveillance for malignant transformation.     

输血相关性铁过载在血液肿瘤中的研究进展

输血相关性铁过载破坏机体铁稳态,从而损害重要脏器结构,导致重要脏器的功能障碍。铁过载影响患者预后,促进骨髓增生异常综合征（ Myelodysplastic syndrome ,MDS）向急性白血病转化,降低造血干细胞移植后患者总生存率,增加造血干细胞移植后治疗相关死亡率,并增加感染的机会。祛铁治疗可延缓骨髓增生异常综合征向急性白血病的进展,延长移植后患者的总生存期,并表现出一定的抗增殖活性。     

Guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload

Experts believe that iron overload is an important problem which could be avoided with suitable treatment. Guidelines on treating myelodysplastic syndromes (MDS) include sections on using iron chelation therapy to prevent or ameliorate transfusional iron overload. The proportion of MDS patients who may benefit from iron chelation therapy is 35-55%, depending on the length of survival necessary for iron to accumulate to a detrimental level. Candidates for iron chelation are mainly patients with dyserythropoietic and cytopenic subtypes of disease, which fall into the International Prognostic Scoring System (IPSS) Low-risk or Intermediate-1-risk categories, with median survival of 3-6 years.     

Anesthetic considerations in the pediatric cancer patient

Cancer is second only to trauma as the leading cause of death in children 1-15 years of age. Pediatric cancer patients have unique physiologic, pharmacologic, and psychologic considerations that present a unique challenge to plan anesthesiologist. A thorough understanding of pediatric tumors, along with chemotherapeutics and their complications, is necessary to plan anesthetic management properly. Special attention is directed to the psychologic needs and preparation of both the patient and parents. Close cooperation and coordination among the pediatric oncologist, surgeon, and anesthesiologist are necessary for safe and expeditious operative care.     

铁过载对造血干细胞移植的影响

铁过载与造血干细胞移植（HSCT）预后关系密切。移植前铁过载可能增加患者HSCT后发生感染、肝静脉闭塞病（VOD）及肝损伤的风险,降低患者移植后总生存（OS）率、无事件生存（EFS）率。移植后铁过载可能降低患者的OS率。祛铁治疗有可能使HSCT患者获益。     

Improving clinical outcome in patients with myelodysplastic syndrome and iron overload using iron chelation therapy

Until recently, little information on the benefits of iron chelation therapy (ICT) in patients with myelodysplastic syndrome (MDS) and iron overload was known. A recent retrospective study showed improved survival in transfusion-dependent patients with MDS (Low or Intermediate-1 risk IPSS) receiving ICT, compared with those not receiving ICT; median overall survival was not reached at 160 months versus 40 months, respectively. Significantly more patients receiving ICT survived to 4 years (80% versus 44%; p < 0.03), suggesting that MDS patients with iron overload might benefit from ICT. Prospective studies to confirm the benefit of ICT in MDS are warranted.     

Increased resistance of peroxisome proliferator-induced hepatic lesions to iron overload in rats

Altered areas (AA), neoplastic nodules (NN) and hepatocellular carcinomas (HCC) induced by chronic administration of ciprofibrate and Wy-14,643 were examined for iron accumulation after systemic iron overload. Eighty percent of AA, 90% NN and 100% HCC showed increased resistance to iron accumulation. However, marked heterogeneity was observed in the amount of iron from area to area within the same lesion with some cells containing no iron, while others showing blue reaction to iron. These findings indicate, that putative preneoplastic and neoplastic hepatic lesions induced by peroxisome proliferators exclude iron in a fashion similar to that of hepatic nodules and carcinomas induced by DNA damaging carcinogens.     

铁过载对性成熟期雄性大鼠生育能力的影响

目的：研究铁过载对性成熟期雄性大鼠生育能力的影响。方法：6~7周龄SPF级雄性Wistar大鼠40只,按体质量随机分为对照组、缺铁组、低剂量铁过载组及高剂量铁过载组,每组10只,经腹腔注射含Fe2+分别为0.9、0.3、9和18 mg的右旋糖酐铁注射液,隔日注射1次,连续6周。于第6周末经腹主动脉采血,采用比色法检测血清铁含量。留取睾丸及附睾,计算脏器指数,制备精子悬液,显微镜下观察精子数量、精子运动情况及精子畸形情况。采用可见光法检测睾丸组织中过氧化氢酶（CAT）水平,黄嘌呤氧化酶法检测睾丸组织中总超氧化物歧化酶（T-SOD）水平,比色法检测睾丸组织中铁含量及谷胱甘肽过氧化物酶（GSH-Px）水平,硫代巴比妥酸法检测睾丸组织中丙二醛（MDA）水平。结果：缺铁组大鼠血清铁含量明显低于对照组（P < 0.01）,而睾丸组织中铁含量与对照组比较,差异无统计学意义（P > 0.05）。低剂量和高剂量铁过载组大鼠血清和睾丸组织中的铁含量均显著高于对照组（P < 0.01）。与对照组相比,缺铁组大鼠的精子数量、精子活动率及精子畸形率的差异均无统计学意义（P > 0.05）。低剂量铁过载组大鼠的精子活动率显著低于对照组（P < 0.01）。高剂量铁过载组大鼠的精子数量和精子活动率显著低于对照组和低剂量铁过载组,且精子畸形率显著高于对照组和低剂量铁过载组（P < 0.05）。缺铁组大鼠睾丸GSH-Px活性显著低于对照组（P < 0.05）。低剂量铁过载组大鼠睾丸GSH-Px活性显著低于对照组,而MDA水平显著高于对照组（P < 0.05）。高剂量铁过载组大鼠睾丸CAT水平及GSH-Px活性均显著低于对照组和低剂量铁过载组,而MDA水平显著高于对照组和低剂量铁过载组（P < 0.05）。结论：铁过载可影响性成熟期雄性大鼠的生育能力,表现为精子数量减少、精子运动率降低以及精子畸形率升高,其原因可能与铁过载所导致的高氧化应激水平有关。     

Iron homeostasis and inherited iron overload disorders: an overview

Iron is an ubiquitous metal of vital importance to the normal physiologic processes of many organisms. Recent discoveries of mutations in genes that lead to inherited iron overload diseases have advanced the understanding of iron homeostasis in humans. This article provides an overview of the human iron cycle, regulation of iron homeostasis, how perturbations in this homeostasis lead to iron overload disease in adults and children, and strategies for diagnosis of inherited iron overload.     

Red blood cell transfusions and iron overload in the treatment of patients with myelodysplastic syndromes

BACKGROUND: Approximately 15,000 new cases of myelodysplastic syndromes (MDS) are expected in the United States each year. METHODS: The mainstay for the management of myelodysplastic syndromes (MDS) is supportive therapy with red blood cell (RBC) transfusions to improve the patient's quality of life. RBC transfusions enable adequate tissue oxygenation and increase hemoglobin levels, improve fatigue, and improve the physical and intellectual activity of patients. Up to 90% of patients with MDS will receive RBC transfusions during the course of their disease, and many will become chronically dependent on transfusions to manage their anemia. These transfusions lead to an accumulation of excess iron that, in turn, can develop into a condition known as iron overload, causing clinical consequences like hypertransaminasemia and cirrhosis, dilated cardiomyopathy, and progressive dysfunction of the endocrine glands. RESULTS: Studies in patients with MDS have indicated that iron overload because of RBC transfusions was an independent, adverse prognostic factor for overall survival (OS) and leukemia-free survival (LFS): OS and LFS were significantly shorter in transfusion-dependent patients with MDS than in those who were not transfusion dependent. CONCLUSIONS: Although the National Comprehensive Cancer Network guidelines for the treatment of patients with MDS recommend the use of RBC transfusions as supportive care, they further recommend that the iron burden of transfused patients be monitored regularly and that iron chelation therapy be considered to maintain serum ferritin levels of <1000 ng/mL.     

Myelodysplastic syndromes: iron overload consequences and current chelating therapies

Chronic red blood cell transfusion support in patients with myelodysplastic syndromes (MDS) is often necessary but may cause hemosiderosis and its consequences. The pathophysiologic effects of iron overload relate to increased non-transferrin bound iron generating toxic oxygen free radicals. Studies in patients with MDS and thalassemia major have shown adverse clinical effects of chronic iron overload on cardiac function in patients who underwent polytransfusion. Iron chelation therapy in patients with thalassemia who were effectively chelated has prevented or partially reversed some of these consequences. A small group of patients with MDS who had undergone effective subcutaneous desferrioxamine (DFO) chelation for 1 to 4 years showed substantial hematologic improvements, including transfusion independence. However, because chronic lengthy subcutaneous infusions of DFO in elderly patients have logistic difficulties, this chelation therapy is generally instituted late in the clinical course. Two oral iron chelators, deferiprone (L1) and deferasirox (ICL670), provide potentially useful treatment for iron overload. This article reviews data indicating that both agents are relatively well tolerated, were at least as effective as DFO for decreasing iron burdens in comparative thalassemia trials, and (for deferiprone) were associated with improved cardiac outcomes. These outcomes could potentially alter the tissue siderosis-associated morbidity of patients with MDS, particularly those with pre-existing cardiac disease.     

Novel treatment options for transfusional iron overload in patients with myelodysplastic syndromes

Red blood cell transfusion dependency is common in myelodysplastic syndromes and is associated with inferior survival. The use of parenteral deferoxamine therapy for transfusional iron overload has been sparse, in part due to cumbersome administration schedules. Deferasirox is an oral iron-chelating agent with favorable pharmacokinetics, including a long half-life allowing continuous 24-hour chelation with once-daily dosing. Deferasirox produces dose-dependent reductions in liver iron content and reduces cardiac iron levels. In-vitro studies with deferasirox suggest improved cardiomyocyte contractility potentially important in reducing excess cardiac mortality noted in transfusion-dependent MDS. Deferasirox has a manageable safety profile with favorable patient satisfaction reports.     

High expression of APAF-1 elevates erythroid apoptosis in iron overload myelodysplastic syndrome

Apoptotic protease-activating factor 1 (APAF-1) is a central component of the intrinsic pathway of apoptosis. Our study aims at searching the role of APAF-1 in iron overload myelodysplastic syndrome (MDS). Erythroid apoptosis rate, mRNA expression levels of APAF-1, and caspase-9 activity were determined by flow cytometry, quantitative real-time PCR, and colorimetric assay in MDS patients, respectively. In addition, K562 and MDS-L cell lines were incubated with different concentrations of ferric ammonium citrate (FAC) or ferric ammonium citrate?+?desferrioxamine (FAC?+?DFO) in vitro to observe the alteration in erythrocyte apoptosis rate, APAF-1 mRNA, and protein expression levels. Moreover, as control, erythroid apoptosis rate and APAF-1 mRNA expression were detected after silencing APAF-1 expression by endoribonuclease-prepared small interfering RNAs (esiRNAs) in K562 and MDS-L cell lines. Both erythroid apoptosis rate and APAF-1 mRNA expression of the iron overload (IO) group were significantly higher than those of the non-IO group (P?<?0.001 and P?<?0.001). There is a significant difference of caspase-9 activity between the IO group and the non-IO group (P?<?0.001). Erythroid apoptosis rate and APAF-1 mRNA expression of K562 and MDS-L cell lines significantly elevated after FAC incubation in different concentrations (P?<?0.001 and P?<?0.001 for K562; P?<?0.001 and P?<?0.001 for MDS-L), while erythroid apoptosis rate and APAF-1 mRNA expression in the FAC?+?DFO group declined (P?<?0.001 and P?<?0.001 for K562; P?<?0.001 and P?<?0.001 for MDS-L). After silencing of APAF-1 expression with specific esiRNAs, erythroid apoptosis rate and APAF-1 mRNA expression of K562 and MDS-L cell lines markedly decreased (P?<?0.001 and P?<?0.001 for K562; P?<?0.001 and P?<?0.001 for MDS-L). APAF-1 plays an important role in iron-induced erythroid apoptosis increase in MDS.